The focus of this project is primarily the function of the yeast mitochondrial ABC transporter encoded by the ATM1 gene. Prior research has demonstrated a role for the TM1 protein in mitochondrial iron homeostasis. Our current hypothesis is that the ATM1 protein is a mitochondrial iron exporter. Deletion of the ATM1 gene in yeast results in mitochondrial iron overload. Associated with the mitochondrial iron accumulation resulting from an ATM1 mutation is a loss of mitochondrial respiratory function and accumulation of mitochondrial DNA mutations. These phenomena are presumed to occur as a result of an increased rate of formation of oxygen radicals catalyzed by the accumulated iron. A human homolog of the yeast ATM1 protein is encoded by the ABC7 gene. We recently identified an inherited mutation in the ABC7 gene as the cause of X-linked sideroblastic anemia and ataxia. Symptoms of male patients affected with this X-linked disorder include a congenital ataxia resulting from a developmental defect in the cerebellum. Patients also have a chronic sideroblastic anemia, which is characterized by the accumulation of iron in the mitochondria of erythroid precursor cells in the bone marrow. The yeast Saccharomyces cerevisiae has been shown to be an excellent model system for the study of mammalian copper and iron metabolism. Many of the yeast proteins which function in cellular iron and copper homeostasis have human homologs which have been implicated in inherited disease. We have shown that the human ABC7 protein is capable of complementing a yeast ATM1 deletion, indicating that the two proteins perform similar functions in the mitochondria. The specific aims of this proposal are; 1) To study the regulation of ATM1 expression and function by heme. 2) To perform a structure-function analysis of the ATM1 homolog of the yeast ATM1 protein. The long term goal of this research is an increased understanding of mitochondrial iron homeostasis, and the role of dysfunction in this process in human disease.